Abstract 813: The protein-like polymer (PLP): A tunable proteomimetic nanoplatform for the development of rationally designed cancer vaccines 
Authors: Max M. Wang, Mi Ran Choi, Brayley Gattis, Bin Zhang, Nathan C. Gianneschi
Journal: Cancer Research (2023)

Abstract Background: Patient-specific cancer vaccines derived from tumor antigen have been a promising therapeutic strategy, however, challenges remain in delivering vaccine components in a coordinated fashion to elicit antitumor responses. To overcome these, we developed rationally designed cancer vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics allowing for sustained targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing peptide antigens were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of PLPs with different sidechain linkage chemistries, degrees of polymerization (DP), and inclusion/exclusion of OEG were made. Cell uptake and functional assays using payload-specific T Cells were conducted to show antigen-specific responses. Ability of PLPs to co-deliver adjuvants in vivo was tested by electrostatically coupling 2’3’ cGAMP, forming stable nanostructures. Results: Conjugating peptide antigens to the PLP backbone using a cleavable disulfide linkage, which reduces intracellularly in APCs, resulted in increased endosomal localization, higher levels of induced T cell proliferation, cytokine production, and expression of activation markers in CTLs and APCs. Incorporating a diluent amount of OEG side chains reduced enzymatic degradation while increasing immunogenicity and APC uptake. Additionally, increasing the DP, and therefore the density of antigen side chains, further improved vaccine efficacy and resistance to proteolysis. Antigen-PLP conjugates enhanced dendritic cell activation and T-cell response only when paired with cells from their cognate system, with no activity in immune cells not expressing receptors for the payload, demonstrating antigen-specificity. Mice bearing established B16F10 tumors treated with gp100-PLPs showed significant increases in survival time and reduced tumor burden with corresponding changes in immune cell profiles. Impressively, mice treated with STING-PLP complexes had significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p &amp;lt;0.0001) following subcutaneous administration of 2’3’ cGAMP, which uncomplexed has a poor PK profile. Current studies looking at the effects of vaccinating with pools of neoantigens multiplexed onto one PLP and generalizability in other tumor models are ongoing. Conclusion: This work validates the ability of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling, highlighting its potential to revolutionize cancer vaccinology. Citation Format: Max M. Wang, Mi Ran Choi, Brayley Gattis, Bin Zhang, Nathan C. Gianneschi. The protein-like polymer (PLP): A tunable proteomimetic nanoplatform for the development of rationally designed cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 813.